Serotonergic involvement in the effects of chronic cold stress on reversal learning in the rats

Abstract

Chronic stress is a risk factor and an antecedent to depression and to dysregulation of brain modulatory systems. Chronic intermittent cold (CIC) stress sensitized the increase in norepinephrine (NE) release in hippocampus and medial prefrontal cortex (mPFC) in response to acute stress (Mana & Grace, 1997. Neuroscience 81:1055). Cognitive performance in an attentional set‐shifting task (AST) can be enhanced by tonic NE transmission in mPFC (Lapiz & Morilak, 2006. Neuroscience 137:1039), and is disrupted by chronic unpredictable stress (Bondi et al. 2007. Neuropsychopharmacol. e‐pub). This study addressed the effects of CIC stress on performance of rats in the AST. Male Sprague‐Dawley rats exposed to a 4°C cold room (6 hr/day × 14 days) were tested in the AST. Analyses showed a significant effect of Stress (P = 0.043), Task (P < 0.0001) and a Stress × Task interaction (P = 0.001), with CIC‐stressed rats requiring more trials during reversal 1. The orbitofrontal cortex (OFC) has previously been implicated in reversal tasks, possibly modulated by serotonin (5‐HT). We showed that 5‐HT depletion with Para‐chlorophenylalanine (200 mg/kg/day, i.p.) induced a similar selective deficit in reversal, while the CIC‐induced impairment in reversal learning was attenuated by the 5‐HT reuptake inhibitor (SSRI) Citalopram (5 mg/kg, i.p.). These results indicate that the CIC stress‐induced impairment in cognitive flexibility may involve an alteration in 5‐HT function in OFC. These deficits may be relevant to the symptoms of neuropsychiatric disorders that respond to SSRI treatment, i.e., depression and anxiety disorders.Support: NIMH grant MH72672 & NARSAD Award to MDLB